EP1256583B1 - Pyrimidine-4-one derivatives, process for their preparation and pharmaceutical compositions containing them - Google Patents

Description

The present invention relates to novel pyrimidin-4-ones derivatives, their method of preparation and the pharmaceutical compositions containing them.

The invention also relates to their use as α ₂ /5-HT _2c mixed ligands.

Derivatives of 1,2,3,3a, 4,9b-hexahydrochromeno [3,4- c ] pyrroles have been described in application EP 691,342 for their serotoninergic antagonist character, and in the application EP 887,350 for their character of dopaminergic ligand D ₃ .

Corticolimbic structures play a vital role in the processes that control impaired functions in psychiatric disorders. In particular, it is now admitted that disruption of monoaminergic transmission is strongly implicated in the etiology of these different disorders. For example in the case of depression, monoaminergic activity is decreased in the frontal cortex, hippocampus and of the nucleus accumbens.

Among the different classes of auto- and heteroreceptors of monoamines involved in regulatory mechanisms, the α ₂ -AR (autoreceptors) and 5-HT _2c receptors have been of paramount importance. These two receptor subtypes act in the same direction by inhibiting dopaminergic and adrenergic transmission. On the one hand, retrocontrol is exerted by autoreceptor α ₂ -AR receptors on noradrenergic neurons (J. Pharmacol Exp Ther, 1994, 270 , 958), and on the other hand, α ₂ -AR receptors. and 5-HT _2c heteroreceptors exert inhibitory control on dopaminergic and noradrenergic transmission (Neuropharmacology, 1997, 36 , 609, J. Psychopharmacol 2000, 14 (2), 114-138).

Compounds binding to one or other of these receptor subtypes have shown their potential, in the past, in the treatment of several pathologies.

Thus, the beneficial role of α ₂ -AR antagonist compounds has been studied in the treatment of cognitive disorders (J. Pharmacol., 1992, 6 , 376), Parkinson's disease (CNS Drugs, 1998, 10 , 189), schizophrenia (Science 1999, 286, 105-107), depression (J. Psychopharmacol. 1996, 10 Suppl. 3: 35-42), disorders of libido and sexual dysfunctions (J. Pharmacol., 1997 , 11 , 72). Similarly, 5HT _2c receptor ligands have been shown to be useful in the treatment of sexual dysfunction (J. Pharmacol., Ibid.) Of Parkinson's disease (Drug News Perspect., 1999, 12 , 477), but also Anxiety (Br J. Pharmacol., 1996, 117 , 427), Depression (Pharmacol Biochem Behav, 1988, 29 , 819-820), Impulsive Disorders (Biol Psych 1993, 33 , 3-14), appetite disorders (British J. Pharmacol 1998, 123 , 1707-1715), sleep disorders (Neuropharmacology 1994, 33 (3/4), 467-471) and schizophrenia ( Neurosci Lett, 1996, 181 , 65).

Compounds possessing a double character of α ₂ -AR and 5-HT _2c antagonists may be of great utility for clinicians, in order to obtain, with the administration of the same compound, a reinforced action while improving the tolerance. This type of compound also has a considerable advantage over the administration of two different products.

The compounds of the invention have an original structure which gives them the character of double α ₂ /5-HT _2c antagonists and are therefore useful in the treatment of depression, impulsive behavior disorders, anxiety, schizophrenia, Parkinson's disease, cognitive disorders, libido disorders, sexual dysfunction, appetite disorders and sleep disorders.

dans laquelle :

R₁, R₂, R₃ et R₄, identiques ou différents, représentent chacun un atome d'hydrogène, d'halogène ou un groupement choisi parmi alkyle (C₁-C₆) linéaire ou ramifié, alkoxy (C₁-C₆) linéaire ou ramifié, polyhalogénoalkyle (C₁-C₆) linéaire ou ramifié, hydroxy, cyano, nitro et amino,
ou bien R₁ avec R₂, R₂ avec R₃ ou R₃ avec R₄ forment ensemble, avec les atomes de carbone qui les portent, un cycle benzénique éventuellement substitué ou hétéroaromatique éventuellement substitué,

X représente un atome d'oxygène ou un groupement méthylène,

A représente une chaíne alkylène (C₁-C₆) linéaire ou ramifiée,

représente un hétérocycle azoté insaturé éventuellement substitué par un ou deux substituants, identiques ou différents, choisis parmi les atomes d'halogène et les groupements alkyle (C₁-C₆) linéaire ou ramifié, hydroxy, alkoxy (C₁-C₆) linéaire ou ramifié, polyhalogénoalkyle (C₁-C₆) linéaire ou ramifié, cyano, nitro, amino, phényle éventuellement substitué, thiényle éventuellement substitué, furyle éventuellement substitué et pyrrolyle éventuellement substitué,

et R₅ représente un groupement alkyle (C₁-C₆) linéaire ou ramifié,

leurs énantiomères, diastéréoisomères ainsi que leurs sels d'addition à un acide ou à une base pharmaceutiquement acceptable,
étant entendu que :

• le terme alkyle (C₁-C₆) désigne une chaíne hydrocarbonée contenant de un à six atomes de carbone,
• le terme alkoxy (C₁-C₆) désigne un groupement alkyle (C₁-C₆)-oxy, contenant de un à six atomes de carbone,
• le terme alkylène (C₁-C₆) désigne une chaíne hydrocarbonée bivalente, contenant de un à six atomes de carbone,
• le terme polyhalogénoalkyle (C₁-C₆) désigne un chaíne carbonée contenant de un à six atomes de carbone et de 1 à 9 atomes d'halogène,
• le terme cycle hétéroaromatique désigne un cycle aromatique de 5 ou 6 chaínons contenant un, deux ou trois hétéroatomes choisis parmi oxygène, azote et soufre,
• le terme hétérocycle azoté insaturé désigne un cycle insaturé à une, deux ou trois insaturations, de 5 à 7 chaínons, contenant un, deux ou trois hétéroatomes, l'un de ces hétéroatomes étant l'atome d'azote, et le ou les hétéroatomes supplémentaires éventuellement présents étant choisis parmi les atomes d'oxygène, d'azote et de soufre,
• le terme éventuellement substitué affecté aux expressions cycle benzénique, cycle hétéroaromatique, phényle, thiényle, furyle ou pyrrolyle, signifie que ces groupements sont éventuellement substitués par un ou deux substituants, identiques ou différents, choisis par les atomes d'halogène et les groupements alkyle (C₁-C₆) linéaire ou ramifié, hydroxy, alkoxy (C₁-C₆) linéaire ou ramifié, polyhalogénoalkyle (C₁-C₆) linéaire ou ramifié, cyano, nitro et amino.

More specifically, the present invention relates to the compounds of formula (I):

in which :

R _1, R _2, R ₃ and R _4, identical or different, each represents a hydrogen atom, halogen or a group selected from alkyl (C ₁ -C ₆₎ linear or branched alkoxy (C ₁ -C ₆ ) linear or branched, linear or branched polyhaloalkyl (C ₁ -C ₆ ), hydroxy, cyano, nitro and amino,
or else R ₁ with R ₂ , R ₂ with R ₃ or R _{3 together} with R ₄ together with the carbon atoms which carry them, an optionally substituted benzene ring or optionally substituted heteroaromatic ring,

X represents an oxygen atom or a methylene group,

A represents a linear or branched (C ₁ -C ₆ ) alkylene chain,

represents an unsaturated nitrogen-containing heterocycle optionally substituted by one or two substituents the same or different, selected from halogen atoms, alkyl (C ₁ -C ₆₎ linear or branched, hydroxy, alkoxy (C ₁ -C ₆₎ linear or branched, linear or branched polyhaloalkyl (C ₁ -C ₆ ), cyano, nitro, amino, optionally substituted phenyl, optionally substituted thienyl, optionally substituted furyl and optionally substituted pyrrolyl,

and R ₅ represents a linear or branched (C ₁ -C ₆ ) alkyl group,

their enantiomers, diastereoisomers and addition salts thereof with a pharmaceutically acceptable acid or base,
Being heard that :

• the term (C ₁ -C ₆ ) alkyl denotes a hydrocarbon chain containing from one to six carbon atoms,
• the term alkoxy (C ₁ -C ₆ ) denotes a (C ₁ -C ₆ ) -alkyloxy group containing from one to six carbon atoms,
• the term alkylene (C ₁ -C ₆ ) denotes a bivalent hydrocarbon chain, containing from one to six carbon atoms,
• the term polyhaloalkyl (C ₁ -C ₆ ) denotes a carbon chain containing from one to six carbon atoms and from 1 to 9 halogen atoms,
• the term heteroaromatic ring designates an aromatic ring of 5 or 6 chains containing one, two or three heteroatoms chosen from oxygen, nitrogen and sulfur,
• the term unsaturated nitrogen heterocycle denotes an unsaturated ring with one, two or three unsaturations, of 5 to 7 chains, containing one, two or three heteroatoms, one of these heteroatoms being the nitrogen atom, and the heteroatom (s); any additional present being chosen from oxygen, nitrogen and sulfur atoms,
• the optionally substituted term assigned to the terms benzene ring, heteroaromatic ring, phenyl, thienyl, furyl or pyrrolyl means that these groups are optionally substituted by one or two substituents, identical or different, chosen by the halogen atoms and the alkyl groups ( C ₁ -C ₆₎ linear or branched, hydroxy, alkoxy (C ₁ -C ₆₎ linear or branched polyhaloalkyl (C ₁ -C ₆₎ linear or branched, cyano, nitro and amino.

Among the pharmaceutically acceptable acids, mention may be made, without limitation, of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, methanesulfonic, camphoric, oxalic, etc.

Among the pharmaceutically acceptable bases, mention may be made, without limitation, of sodium hydroxide, potassium hydroxide, triethylamine, etc.

Among the heteroaromatic rings, mention may be made, without limitation, of thiophene, pyridine, furan, pyrrole, imidazole, oxazole, isoxazole, thiazole, isothiazole, pyrimidine.

Preferred unsaturated nitrogen heterocycles are 1,2-dihydropyridine, 2,3-dihydro-1,3-thiazole and 2,3-dihydrooxazole.

By compound (3aα, 9bα) or (3aβ, 9bβ) is meant compound whose ring junction corresponding is cis configuration.

By compound (3aα, 11cα) or (3aβ, 11cβ) is meant compound whose ring junction corresponding is cis configuration.

By compound (3aα, 9bβ) or (3aβ, 9bα) is meant compound whose corresponding junction cycle is trans.

By compound (3aα, 11cβ) or (3aβ, 11cα) is meant compound whose junction corresponding cycle is trans.

In the preferred compounds of formula (I), R ₁ , R ₂ , R ₃ and R ₄ , which are identical or different, each represent a hydrogen atom or a linear or branched (C ₁ -C ₆ ) alkyl, alkoxy ( C ₁ -C ₆ ) linear or branched or hydroxy.

Preferred compounds of the invention are those for which R ₁ and R ₂ together with the carbon atoms which carry them, a benzene ring and R ₃ , R ₄ each represent a hydrogen atom.

Preferably, X represents an oxygen atom.

Advantageously, the invention relates to the compounds of formula (I) for which A represents an ethylene, propylene or butylene chain.

représente le groupement suivant

éventuellement substitué, par un ou deux substituants, identiques ou différents, choisis parmi les atomes d'halogène et les groupements alkyle (C₁-C₆) linéaire ou ramifié, hydroxy, alkoxy (C₁-C₆) linéaire ou ramifié, polyhalogénoalkyle (C₁-C₆) linéaire ou ramifié, cyano, nitro, amino et thiènyle. More particularly, the invention relates to the compounds of formula (I) for which

represents the next grouping

optionally substituted by one or two substituents the same or different, selected from halogen atoms, alkyl (C ₁ -C ₆₎ linear or branched, hydroxy, alkoxy (C ₁ -C ₆₎ linear or branched polyhaloalkyl (C ₁ -C ₆ ) linear or branched, cyano, nitro, amino and thienyl.

représente le groupement suivant

éventuellement substitué par un ou deux substituants, identiques ou différents, choisis parmi les atomes d'halogène et les groupements alkyle (C₁-C₆) linéaire ou ramifié, hydroxy, alkoxy (C₁-C₆) linéaire ou ramifié, polyhalogénoalkyle (C₁-C₆) linéaire ou ramifié, cyano, nitro et amino.Other preferred compounds of the invention relate to the compounds of formula (I) for which

represents the next grouping

optionally substituted by one or two substituents the same or different, selected from halogen atoms, alkyl (C ₁ -C ₆₎ linear or branched, hydroxy, alkoxy (C ₁ -C ₆₎ linear or branched polyhaloalkyl ( C ₁ -C ₆ ) linear or branched, cyano, nitro and amino.

représente le groupement suivant

éventuellement substitué en position 2' par un atome d'halogène ou un groupement choisi parmi alkyle (C₁-C₆) linéaire ou ramifié, cyano et thiènyle.The present invention relates more particularly to the compounds of formula (I) for which A represents an ethylene chain, X represents an oxygen atom, R ₅ represents a methyl group and

represents the next grouping

optionally substituted in the 2 'position by a halogen atom or a group chosen from linear or branched (C ₁ -C ₆ ) alkyl, cyano and thienyl.

• la 3-[2-((3aα,9bα)-9-méthoxy-1,3a,4,9b-tétrahydrochroméno[3,4-c]pyrrol-2(3H)-yl)-éthyl]-2-méthyl-4H-pyrido[1,2-a]pyrimidin-4-one, ainsi que ses énantiomères, diastéréoisomères et ses sels d'addition à un acide pharmaceutiquement acceptable,
• la 3-[2-((3aα,11cα)-1,3a,4,11c-tétrahydrobenzo[5,6]chroméno[3,4-c]pyrrol-2(3H)-yl)-éthyl]-2-méthyl-4H-pyrido[1,2-a]pyrimidin-4-one, ainsi que ses énantiomères et ses sels d'addition à un acide pharmaceutiquement acceptable,
• et la 3-[2-((3aβ,11cα)-1,3a,4,11c-tétrahydrobenzo[5,6]chroméno[3,4-c]pyrrol-2(3H)-yl)éthyl]-2-méthyl-4H-pyrido[1,2-a]pyrimidin-4-one, ainsi que ses énantiomères et ses sels d'addition à un acide pharmaceutiquement acceptable.

Among the preferred compounds of the invention, mention may be made more particularly of:

• 3- [2 - ((3aα, 9bα) -9-methoxy-1,3a, 4,9b-tetrahydrochromo [3,4- c ] pyrrol-2 ( 3H ) -yl) ethyl] -2-methyl 4 H -pyrido [1,2- a ] pyrimidin-4-one, as well as its enantiomers, diastereoisomers and its addition salts with a pharmaceutically acceptable acid,
• 3- [2 - ((3aα, 11cα) -1,3a, 4,11c-tetrahydrobenzo [5,6] chromeno [3,4- c ] pyrrol-2 ( 3H ) -yl) -ethyl] -2 methyl-4 H -pyrido [1,2-a] pyrimidin-4-one and its enantiomers and its addition salts with a pharmaceutically acceptable acid,
• and 3- [2 - ((3aβ, 11cα) -1,3a, 4,11c-tetrahydrobenzo [5,6] chromeno [3,4- c ] pyrrol-2 ( 3H ) -yl) ethyl] -2 4-methyl- 4H- pyrido [1,2- a ] pyrimidin-4-one, as well as its enantiomers and its addition salts with a pharmaceutically acceptable acid.

   dans laquelle R₁, R₂, R₃, R₄ et X sont tels que définis dans la formule (I),
à une hydrogénation catalytique, pour conduire au composé de formule (III) :

   dans laquelle R₁, R₂, R₃, R₄ et X sont tels que définis précédemment,
que l'on met en réaction, soit avec un composé de formule (IV) :

dans laquelle A, B et R₅ sont tels que définis dans la formule (I), et Y₁ représente un groupement partant tel que, par exemple, un atome d'halogène ou un groupement tosylate, triflate ou mésylate,
soit, dans des conditions d'amination réductrice, avec un composé de formule (V) :

dans laquelle B et R₅ sont tels que définis dans la formule (I), et A' représente une liaison ou une chaíne alkylène (C₁-C₅) linéaire ou ramifiée,
pour conduire au composé de formule (I), que l'on purifie, le cas échéant, selon une technique classique de purification, dont on sépare, si on le souhaite, les stéréoisomères selon une technique classique de séparation, et que l'on transforme, si on le souhaite, en ses sels d'addition à un acide ou à une base pharmaceutiquement acceptable.The invention also extends to a process for preparing the compounds of formula (I), characterized in that a compound of formula (II) is subjected to:

in which R ₁ , R ₂ , R ₃ , R ₄ and X are as defined in formula (I),
to catalytic hydrogenation, to yield the compound of formula (III):

in which R ₁ , R ₂ , R ₃ , R ₄ and X are as defined above,
that is reacted, either with a compound of formula (IV):

in which A, B and R ₅ are as defined in formula (I), and Y ₁ represents a leaving group such as, for example, a halogen atom or a tosylate, triflate or mesylate group,
or, under reductive amination conditions, with a compound of formula (V):

in which B and R ₅ are as defined in formula (I), and A 'represents a bond or a linear or branched (C ₁ -C ₅ ) alkylene chain,
to give the compound of formula (I), which is purified, if appropriate, according to a conventional purification technique, the stereoisomers are separated, if desired, according to a conventional technique of separation, and that one if desired, converts to its addition salts with a pharmaceutically acceptable acid or base.

   dans laquelle R₁, R₂, R₃ et R₄ sont tels que définis précédemment, sur lequel on effectue une cycloaddition avec la N-benzyl-N-(méthoxyméthyl)-triméthylsilylméthylamine, dans les conditions décrites par K. Achiwa et coll. (Chem. Pharm. Bull. 1985, 33 (7), 2762-66),
pour conduire au composé de formule (VII) :

   dans laquelle R₁, R₂, R₃ et R₄ sont tels que définis précédemment,
que l'on transforme ensuite, par réduction suivie de la déprotection de la fonction phénol, en composé de formule (VIII) :

   dans laquelle R₁, R₂, R₃ et R₄ sont tels que définis précédemment,
qui est ensuite transformé en composé de formule (IIa) par une réaction de Mitsunobu.The compounds of formula (II) for which X represents an oxygen atom (compounds of formula (IIa)) can be obtained from the compound of formula (VI):

in which R ₁ , R ₂ , R ₃ and R ₄ are as defined above, on which cycloaddition is carried out with N-benzyl-N- (methoxymethyl) -trimethylsilylmethylamine under the conditions described by K. Achiwa et al. (Chem Pharm Bull 1985, 33 (7), 2762-66),
to yield the compound of formula (VII):

in which R ₁ , R ₂ , R ₃ and R ₄ are as defined above,
that is then transformed, by reduction followed by the deprotection of the phenol function, into a compound of formula (VIII):

in which R ₁ , R ₂ , R ₃ and R ₄ are as defined above,
which is then converted to a compound of formula (IIa) by a Mitsunobu reaction.

The configuration of the ring junction of the compound of formula (IIa) thus obtained is determined by the configuration (Z or E) of the compound of formula (VI) used.

   dans laquelle R₁, R₂, R₃ et R₄ sont tels que définis précédemment,
que l'on oxyde en composé de formule (X) :

   dans laquelle R₁, R₂, R₃ et R₄ sont tels que définis précédemment,
que l'on met en réaction avec le propiolate de méthyle, pour conduire à la coumarine de formule (XI) :

   dans laquelle R₁, R₂, R₃ et R₄ sont tels que définis précédemment,
que l'on soumet :

• soit, lorsqu'on veut accéder à un composé de formule (IIa) dont la jonction de cycle est trans, à une réaction avec le méthanolate de sodium, puis à une réaction de cycloaddition avec la N-benzyl-N-(méthoxyméthyl)-triméthylsilylméthylamine, dans les conditions décrites par K. Achiwa et coll. (Chem. Pharm. Bull. 1985, 33 (7), 2762-66), suivie d'une réaction de réduction,
  pour conduire à un composé de formule (VIII) dont la configuration est trans, qui est ensuite transformé en composé de formule (IIa) trans par une réaction de Mitsunobu,
• soit, lorsqu'on veut accéder à un composé de formule (IIa) dont la jonction de cycle est cis, à une réaction de cycloaddition avec la N-benzyl-N-(méthoxyméthyl)-triméthylsilylméthylamine, dans les conditions décrites par K. Achiwa et coll. (Chem. Pharm. Bull. 1985, 33 (7), 2762-66),
  pour conduire au composé de formule (XII), dont la jonction de cycle est cis :
  

   dans laquelle R₁, R₂, R₃ et R₄ sont tels que définis précédemment,
que l'on réduit ensuite en composé de formule (VIII) dont la configuration est cis, qui est ensuite transformé en composé de formule (IIa) cis par une réaction de Mitsunobu.The compounds of formula (IIa) can also be obtained from the compound of formula (IX):

in which R ₁ , R ₂ , R ₃ and R ₄ are as defined above,
that is oxidized compound of formula (X):

in which R ₁ , R ₂ , R ₃ and R ₄ are as defined above,
that one reacts with methyl propiolate, to lead to the coumarin of formula (XI):

in which R ₁ , R ₂ , R ₃ and R ₄ are as defined above,
that we submit:

• or, when one wants to access a compound of formula (IIa) whose ring junction is trans, to a reaction with sodium methanolate, then to a cycloaddition reaction with N-benzyl-N- (methoxymethyl) - trimethylsilylmethylamine under the conditions described by K. Achiwa et al. (Chem Pharm Bull 1985, 33 (7), 2762-66), followed by a reduction reaction,
  to yield a compound of formula (VIII) whose configuration is trans, which is then converted to a compound of formula (IIa) trans by a Mitsunobu reaction,
• or, when it is desired to access a compound of formula (IIa) whose ring junction is cis, to a cycloaddition reaction with N-benzyl-N- (methoxymethyl) -trimethylsilylmethylamine, under the conditions described by K. Achiwa et al. (Chem Pharm Bull 1985, 33 (7), 2762-66),
  to yield the compound of formula (XII), whose ring junction is cis:
  

in which R ₁ , R ₂ , R ₃ and R ₄ are as defined above,
that is then reduced to a compound of formula (VIII) whose configuration is cis, which is then converted into compound of formula (IIa) cis by a Mitsunobu reaction.

   dans laquelle R₁, R₂, R₃ et R₄ sont tels que définis dans la formule (I),
que l'on fait réagir avec l'acrylate d'éthyle pour conduire au composé de formule (XIV) :

   dans laquelle R₁, R₂, R₃ et R₄ sont tels que définis précédemment,
que l'on transforme, par réduction suivie d'une saponification, en composé de formule (XV) :

   dans laquelle R₁, R₂, R₃ et R₄ sont tels que définis précédemment,
que l'on cyclise en composé de formule (XVI) :

   dans laquelle R₁, R₂, R₃ et R₄ sont tels que définis précédemment,
que l'on transforme ensuite en composé de formule (XVII) :

   dans laquelle R₁, R₂, R₃ et R₄ sont tels que définis précédemment,
puis, par addition de cyanure de lithium, en composé de formule (XVIII) :

   dans laquelle R₁, R₂, R₃ et R₄ sont tels que définis précédemment,
dont on transforme les groupements cyano en groupements carboxy, avant de les condenser pour conduire au composé de formule (XIX) :

   dans laquelle R₁, R₂, R₃ et R₄ sont tels que définis précédemment,
que l'on fait ensuite réagir avec la benzylamine, pour conduire au composé de formule (XX) :

   dans laquelle R₁, R₂, R₃ et R₄ sont tels que définis précédemment,
que l'on transforme par réduction en composé de formule (IIb).The compounds of formula (II) for which X represents a methylene group (compounds of formula (IIb)) can be obtained from the compound of formula (XIII):

in which R ₁ , R ₂ , R ₃ and R ₄ are as defined in formula (I),
that is reacted with ethyl acrylate to yield the compound of formula (XIV):

in which R ₁ , R ₂ , R ₃ and R ₄ are as defined above,
that is converted, by reduction followed by saponification, into a compound of formula (XV):

in which R ₁ , R ₂ , R ₃ and R ₄ are as defined above,
that is cyclized to a compound of formula (XVI):

in which R ₁ , R ₂ , R ₃ and R ₄ are as defined above,
that is then transformed into a compound of formula (XVII):

in which R ₁ , R ₂ , R ₃ and R ₄ are as defined above,
then, by addition of lithium cyanide, to a compound of formula (XVIII):

in which R ₁ , R ₂ , R ₃ and R ₄ are as defined above,
whose cyano groups are converted into carboxy groups, before condensing them to yield the compound of formula (XIX):

in which R ₁ , R ₂ , R ₃ and R ₄ are as defined above,
that is then reacted with benzylamine, to yield the compound of formula (XX):

in which R ₁ , R ₂ , R ₃ and R ₄ are as defined above,
that is converted by reduction into a compound of formula (IIb).

The invention also extends to pharmaceutical compositions containing as a principle a compound of formula (I) with one or more inert, non-toxic and pharmaceutically acceptable. Among the pharmaceutical compositions according to the invention, more particularly those which are suitable for oral, parenteral (intravenous, intramuscular or subcutaneous), nasal, single or coated tablets, sublingual tablets, capsules, lozenges, suppositories, creams, ointments, dermal gels, preparations injectables, oral suspensions, etc.

The useful dosage is adaptable according to the nature and the severity of the affection, the way administration and the age and weight of the patient and the possible treatments associates. This dosage varies from 0.5 mg to 2 g per 24 hours in one or more doses.

The following examples illustrate the invention.

The starting materials used are known products or prepared according to known preparations.

The structures of the compounds described in the examples were determined according to usual spectrometric techniques (infrared, NMR, mass spectrometry).

EXAMPLE 1 : 3- [2 - ((3aα, 9bα) -9-Methoxy-1,3a, 4,9b-tetrahydrochromeno [3,4- vs ] pyrrol-2 (3 H ) -Yl) -ethyl] -2-methyl-4 H pyrido [1,2- at ] Pyrimidin-4-one, dihydrochloride Stage A (3α, 4α) -1-Benzyl-4- (2,6-dimethoxyphenyl) -3-pyrrolidinecarboxylate methyl

To a solution, cooled to 5 ° C., containing 120 mmol of the methyl ester of cis- (2,6-dimethoxy) cinnamic acid, and 0.1 ml of trifluoroacetic acid in 150 ml of acetate of ethyl are slowly added 100 mmol of N-benzyl-N- (methoxymethyl) triméthylsilylméthylamine. The reaction medium is heated from 30 ° C. to 55 ° C. in 75 minutes. 0.75 g of potassium carbonate are then added and the whole is maintained under stirring 15 minutes. After filtration and evaporation of the solvents, the residue is taken up by 100 ml of ethyl acetate and the solution brought to 50 ° C. 110 mmol of oxalic acid in solution in 100 ml of acetone are then added with vigorous stirring. This one is maintained 15 hours. After filtration and then washing with ether, the oxalate obtained is treated with two equivalents of 1N potassium hydroxide to yield the expected product.

Stage B : (3α, 4α) -1-Benzyl-3-hydroxymethyl-4- (2,6-dimethoxyphenyl) -pyrrolidine

To 120 mmol of lithium aluminum hydride suspended in 800 ml of tetrahydrofuran at +5 ° C. are added 100 mmol of the compound obtained in the preceding stage in solution in 400 ml of tetrahydrofuran. After an hour of agitation at this temperature, the medium is treated by slow addition of 11 ml of water, 15 ml of 2N sodium hydroxide and 26 ml of water. The medium is stirred for 10 hours and then filtered. The solvent is evaporated to lead to the expected product.

Stage C : (3α, 4α) -1-Benzyl-3-hydroxymethyl-4- (2,6-dihydroxyphenyl) -pyrrolidine

To 8.9 mmol of the compound obtained in the preceding stage in 170 ml of dichloromethane, 44.5 ml of a 1M solution of boron tribromide in dichloromethane are added. The The reaction medium is refluxed for 8 hours and then treated with concentrated sodium hydroxide during one o'clock. The medium is then neutralized with hydrochloric acid. After extraction dichloromethane, the expected product is obtained after purification of the residue by chromatography on silica (eluent: 95/5 dichloromethane / methanol).

Stage D (3αα, 9bα) -2-Benzyl-9-hydroxy-1,2,3,3a, 4,9b-hexahydrochromo [3,4-c] pyrrole hydrochloride

At 80 mmol of the compound obtained in the preceding stage in 1 liter of tetrahydrofuran are successively added 120 mmol of diethylazodicarboxylate and 120 mmol of triphenylphosphine. The medium is stirred at ambient temperature for 15 hours. The solvent is evaporated and the crude product is taken up in 1 liter of isopropyl ether and heated to reflux for an hour. The precipitate obtained is removed and the filtrate is concentrated before to be chromatographed (eluent: cyclohexane / ethyl acetate 70/30). The product obtained is salified with hydrochloric acid.

Stadium E (3aα, 9bα) -2-Benzyl-9-methoxy-1,2,3,3a, 4,9b-hexahydrochromo [3,4-c] pyrrole hydrochloride

11.6 mmol of the compound obtained in the preceding stage in 50 ml of dimethylformamide are added to a solution containing 14 mmol of sodium hydride in 50 ml of dimethylformamide. After stirring for 30 minutes, 11.6 mmol of methyl iodide are added. After 1 hour at room temperature and then hydrolyzed, the solvents are evaporated. The residue is then taken up in water. After extraction with ether, drying and evaporation, the expected product is obtained after purification of the residue by chromatography on a silica column using a cyclohexane / ethyl acetate mixture (75/25) as eluent. Elemental microanalysis: VS% H% NOT% Cl% calculated 68.77 6.68 4.22 10.68 find 68.66 4.48 4.45 10.97

Stade F : (3aα, 9bα) -9-Methoxy-1,2,3,3a, 4,9b-hexahydrochromeno [3,4-c] pyrrole

50 mmol of the compound obtained in the preceding stage is dissolved in a mixture of 200 ml of methanol and 50 ml of water. 50 mmol of a 5 N solution of hydrochloric acid in ethanol are added. After addition of 2 grams of palladium dihydroxide, the The reaction medium is placed under a hydrogen atmosphere. After absorption of the volume theoretical hydrogen, the catalyst is filtered and the filtrate is evaporated. The residue obtained is treated with 1N sodium hydroxide and extracted with dichloromethane to yield the product expected.

Stade G : 3- [2 - ((3aα, 9bα) -9-methoxy-1,3a, 4,9b-tetrahydrochromo [3,4-c] pyrrol-2 (3H) -yl) -ethyl] -2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one, dihydrochloride

7 mmol of potassium carbonate are added to 7 mmol of the compound obtained in the preceding stage in 100 ml of acetonitrile. The medium is brought to 60 ° C. 7 mmol of 3- (2-chloroethyl) -2-methylpyrido [1,2-a] pyrimidin-4-one (prepared according to Liebigs Ann Chem 1973, 103-110) are then added all at once. The medium is heated at 80 ° C. for 18 hours. After cooling and adding water, the medium is extracted with dichloromethane and then washed and dried. After filtration and evaporation of the solvents, the residue obtained is purified by chromatography on silica (eluent: 95/5 dichloromethane / methanol). The product obtained is salified with hydrochloric acid. Elemental microanalysis: VS% H% NOT% Cl% calculated 59.49 5.86 9.05 15.27 find 59.57 5.89 9.09 15,41

EXAMPLE 2 : 3- [2 - ((3aα, 9bα) -6,8-dimethoxy-7-methyl-1,3a, 4,9b-tetrahydrochromo [3,4-b] vs ] Pyrrol-2 (3 H ) -Yl) -ethyl] -2-methyl-4 H pyrido [1,2- at ] pyrimidin-4-one, sesquifumarate Stage A 2,4-Dimethoxy-3-methylphenol

To 416 mmol of 2,4-dimethoxy-3-methyl-benzaldehyde dissolved in 200 ml of dichloromethane are added 624 mmol of meta-chloroperbenzoic acid. The reaction medium is refluxed for 5 hours before being filtered. The filtrate is washed with 3 times 200 ml of a saturated solution of NaHCO ₃ and then dried over magnesium sulfate. After evaporation of the solvent, the crude product is taken up in 400 ml of methanol. 624 mmol of a 10% KOH solution are added. The medium is stirred for one hour and then brought to pH = 4 with a 1N solution of hydrochloric acid. After one hour of agitation, the volume is reduced to 1/3. The crude product is taken up in 400 ml of water and extracted with dichloromethane. The organic phases are collected and dried. After evaporation of the solvents, the residue obtained is purified by chromatography on a silica column (eluent: cyclohexane / ethyl acetate 90/10) to yield the expected product.

Stage B : 6,8-Dimethoxy-7-methyl-coumarin

At 270 mmol of the compound obtained in the preceding stage in solution in 500 ml of acid anhydrous methanesulfonic acid is added 270 mmol of methyl propiolate. The environment The reaction mixture is heated at 90 ° C. for 30 minutes and then cooled to 0 ° C. After an addition water slowly, the medium is extracted with dichloromethane. The organic phases are collected, washed with a 1N solution of sodium hydroxide and then dried. After evaporation of solvents, the residue obtained is triturated in ethyl ether and then filtered to yield the expected product.

Stage C (3α, 4α) -1-Benzyl-3-hydroxymethyl-4- (3,5-dimethoxy-2-hydroxy-4-tolyl) -pyrrolidine

The expected product is obtained according to the process described in Steps A and B of Example 1 from the compound obtained in the previous stage.

Stage D (3aα, 9bα) -2-Benzyl-6,8-dimethoxy-7-methyl-1,2,3,3a, 4,9b-hexahydrochromeno [3,4-c] pyrrole, hydrochloride

The expected product is obtained according to the process described in Step D of Example 1 from the compound obtained in the preceding stage. Elemental microanalysis: VS% H% NOT% Cl% calculated 67.10 6.97 3.73 9.43 find 66.90 7.00 3.92 9.57

Stadium E : (3aα, 9bα) -6,8-Dimethoxy-7-methyl-1,2,3,3a, 4,9b-hexahydrochromeno [3,4-c] pyrrole

The expected product is obtained according to the process described in Stage F of Example 1 from of the compound obtained in the preceding stage.

Stade F : 3- [2 - ((3aα, 9bα) -6,8-Dimethoxy-7-methyl-1,3a, 4,9b-tetrahydrochromeno [3,4-c] pyrrol 2 (3H) -yl) -ethyl] -2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one, sesquifumarate

The expected product is obtained according to the process described in Step G of Example 1 from the compound obtained in the preceding stage. The product obtained is salified with fumaric acid. Elemental microanalysis: VS% H% NOT% calculated 61.07 5.80 6.89 find 61.73 6.03 7.19

EXAMPLE 3 3- [2- (1,3a, 4,11c-Tetrahydrobenzo [5,6] chromeno [3,4- vs ] pyrrol-2 (3 H ) -Yl) -ethyl] -2-methyl-4 H pyrido [1,2- at ] Pyrimidin-4-one, fumarate Stage A 1,2,3,3a, 4,11c-Hexahydrobenzo [5,6] chromeno [3,4-c] pyrrole

The expected product is obtained according to the process described in Steps C to F of Example 2 from benzo [ f ] chromen-3-one.

Stage B 3- [2- (1,3a, 4,11c-Tetrahydrobenzo [5,6] chromeno [3,4-c] pyrrol-2 (3H) -yl) -ethyl] -2-methyl-4H-pyrido [ 1,2-a] pyrimidin-4-one, fumarate

The expected product is obtained according to the process described in Step G of Example 1 from the compound obtained in the preceding stage. Elemental microanalysis: VS% H% NOT% calculated 68.30 5.54 7.96 find 67.87 5.57 7.79

EXAMPLE 4 : 6- [2 - ((3aα, 11cα) -1,3a, 4,11c-tetrahydrobenzo [5,6] chromeno [3,4- vs ] pyrrol-2 (3 H ) -Yl) -ethyl] -7-methyl-5 H - [1,3] thiazolo [3,2 at ] Pyrimidin-5-one, fumarate

The expected product is obtained according to the process described in Step G of Example 1, using as starting materials the compound described in Step A of Example 3 and 6- (2-chloro-ethyl) -7- methyl-thiazolo [3,2- a ] pyrimidin-5-one. The product obtained is salified with fumaric acid. Elemental microanalysis: VS% H% NOT% S% calculated 63.03 5.10 7.87 6.01 find 62.91 5.08 7.77 5.83

EXAMPLE 5 : 3- [3 - ((3aα, 11cα) -1,3a, 4,11c-tetrahydrobenzo [5,6] chromeno [3,4- vs ] pyrrol-2 (3 H ) -Yl) propyl] -2-methyl-4 H pyrido [1,2- at ] Pyrimidin-4-one, hemifumarate Stage A 3- (2-Methyl) -4-oxo-pyrido [1,2-a] pyrimidin-3-yl) -propionaldehyde

To 60 mmol of 3- (2-chloro-ethyl) -2-methyl-pyrido [1,2-a] pyrimidin-4-one (prepared according to Liebigs Ann. Chem. 1973, 103-110) in 140 ml of dimethylsulfoxide are added 120 mmol of potassium cyanide. The reaction medium is brought to 100 ° C. for 3 hours. After evaporation of the dimethylsulfoxide, the crude product is taken up by dichloromethane and water, extracted with dichloromethane. The organic phases are washed and dried. The residue is purified by chromatography on silica (eluent: dichloromethane / methanol 95/5) and the product obtained is dissolved in 100 ml of dichloromethane. The medium is cooled to -70 ° C., 120 mmol of diisobutylaluminium hydride are introduced. After stirring for 2 hours at this temperature, the medium is treated with 50 ml of methanol and 100 ml of water, then the organic phase is washed and dried to lead to the expected product.

Stage B : 3- [3 - ((3aα, 11cα) -1,3a, 4,11c-Tetrahydrobenzo [5,6] chromeno [3,4-c] pyrrol-2 (3H) -yl) propyl] -2-methyl -4H-pyrido [1,2-α] pyrimidin-4-one, hemifumarate

10 mmol of the compound described in Step A of Example 3 in solution in 1,2-dichloroethane are added 10 mmol of the compound obtained in the preceding stage, followed by 14 mmol of sodium triacetoxyborohydride. After stirring for 4 hours, water is added, then the reaction mixture is decanted and extracted with dichloromethane. The combined organic phases are dried, then filtered and evaporated. The residue thus obtained is purified by chromatography on silica (eluent: 95/5 dichloromethane / methanol) to give, after salification with fumaric acid, the expected product. Elemental microanalysis: VS% H% NOT% calculated 72,03 6.04 8.69 find 71.68 5.95 8.59

EXAMPLE 6 3- {2 - [(3aα, 11cα) -1,3,3a, 4,5,11c-hexahydro-2 H naphtho [1,2- e ] Isoindol-2-yl] ethyl} -2-methyl-4 H pyrido [1,2- at ] Pyrimidin-4-one, fumarate Stage A : 2-Chloromethyl-naphthalene

To 1.26 moles of naphthalen-2-yl-methanol in 1.5 liters of toluene are slowly added 3.8 moles of thionyl chloride. The medium is then refluxed for two hours. After cooling, the solvent is evaporated. The crude product is taken up twice with toluene and evaporated. The oil obtained is taken up in dicholoromethane, washed and dried. After filtration and evaporation, the oil obtained is distilled to yield the expected product.
Boiling point: 118 ° C at 0.09 mm Hg

Stage B Ethyl 4- (2-Naphtyl) -2-butenoate

To 863 mmol of the compound obtained in the preceding stage in 206 ml of tri-butylamine are 1.07 moles of ethyl acrylate and 10 mmol of palladium acetate were added. The environment The reaction mixture is refluxed for five hours. After cooling, the medium is hydrolysed and extracted once with dichloromethane. The organic phase is washed with 1N hydrochloric acid solution and then with water before being dried. The product is purified by chromatography on silica (eluent: cyclohexane / ethyl acetate 95/5) to lead to the expected product.

Stage C Ethyl 4- (2-Naphtyl) -2-butanoate

490 mmol of the compound obtained in the preceding stage in 3 l of ethanol are added 7 grams of 10% palladium on charcoal. The medium is put under atmosphere hydrogen. After absorption of the theoretical amount of hydrogen, the medium is filtered and the solvent is evaporated to yield the expected product.

Stage D : 4- (2-Naphthyl) -2-butanoic acid

484 mmol of the compound obtained in the preceding stage in 1.5 liters of ethanol, are 490 ml of a standard 2 N sodium hydroxide solution are added. The medium is reflux for an hour. The ethanol is then evaporated. The pH is brought to a value of 5-6 with 1N hydrochloric acid. The precipitate formed is filtered off and washed with water to lead to the expected product.

Stadium E : 2,3-Dihydro-4 (1H) -phenanthrenone

550 mg of the compound obtained at the stage are added to 550 g of polyphosphoric acid previous. The reaction medium is heated at 80 ° C. for 3 hours and then poured over the ice cream. After stirring for one hour, the precipitate formed is filtered off, washed with water and dried for lead to the expected product.

Stade F : 1,2-Dihydro-4-phenanthrene-carbonitrile

To 207 mmol of the compound obtained in the preceding stage in 500 ml of tetrahydrofuran are successively added 243 mmol of trimethylsilane cyanide and 16 mmol of a 0.5M solution of lithium cyanide in dimethylformamide. The reaction medium is stirred for 2 hours and then poured onto ice and extracted 4 times with ether. The organic phases are collected and washed with water before being dried. After filtration, the solvents are evaporated. The residue is dissolved in 325 ml of pyridine. 42 ml of POCl ₃ are added. The medium is heated at 100 ° C. for 3 hours and then cooled before being poured into 400 ml of ice-cold hydrochloric acid. After addition of dichloromethane, the medium is decanted and then extracted with dichloromethane. The combined organic phases are washed and then dried. After filtration, the solvents are evaporated. The residue obtained is purified by chromatography on silica (eluent: cyclohexane / dichloromethane: 70/30) to yield the expected product.

Stade G 1,2,3,4-Tetrahydro-phenanthrene-3,4-dicarbonitrile

87 mmol of acetic acid are added 105 mmol of a 0.5 M solution of lithium cyanide, then, at 5.degree. C., 82 mmol of the compound obtained in the preceding stage in solution in 500 ml of dimethylformamide. The reaction medium is brought to 100 ° C. for two hours before being chilled and then dried and poured on ice. The precipitate obtained is filtered and washed to yield the expected product.

Stage H 1,2,3,4-tetrahydro-phenanthrene-3,4-dicarboxylic acid

At 68 mmol of the compound obtained in the preceding stage are added successively ml of acetic acid and then 84 ml of concentrated hydrochloric acid. The reaction medium is refluxed for 5 days before being cooled and poured on a liter of water. The product is extracted with ethyl acetate. The organic phases are collected and dried. After filtration and evaporation of the solvent, the residue obtained is purified by chromatography (eluent: dichloromethane / methanol / acetic acid: 95/5 / 0.5) to yield the product expected.

Stage I : (3aα, 11cα) -3a, 4,5,11c-Tetrahydrophenantro [3,4-c] furan-1,3-dione

To 37 mmol of the compound obtained in the preceding stage are added 1.67 moles of acetic anhydride. The reaction medium is refluxed for 2 h and then evaporated at dry. The residue obtained is triturated in ether to yield the expected product in the form of crystals.

Stage J (3αα, 11αα) -2-Benzyl-3α, 4,5,11c-tetrahydro-1H-naphtho [1,2-e] isoindole-1,3 (2H) -dione

To 18 mmol of the compound obtained in the preceding stage in 400 ml of toluene are added 18 mmol of benzylamine. The reaction medium is refluxed during 30 hours. 70 ml of a 0.1 N solution of hydrochloric acid are added. The middle is decanted. The organic phase is dried, filtered and evaporated. The resulting residue is purified by chromatography on silica (eluent: dichloromethane / cyclohexane: 60/40) to lead to the expected product.

K Stadium (3aα, 11cα) -2-Benzyl-2,3,3a, 4,5,11c-hexahydro-1H-naphtho [1,2-e] isoindole hydrochloride

93 ml of aluminum-lithium hydride are poured into 180 ml of anhydrous ether. After cooling to 10 ° C., 15.5 mmol of the compound obtained in the preceding stage in solution in 250 ml of dichloromethane are added. The reaction medium is stirred at room temperature for 2 hours and is then cooled to -10 ° C. 90 ml of water are added slowly. The gel obtained is filtered and washed extensively with dichloromethane. The organic phases and the filtrate are collected and decanted. The organic phase is dried, filtered and evaporated. The residue obtained is purified by chromatography on silica (eluent: cyclohexane / ethyl acetate 80/20). The product obtained is salified with hydrochloric acid. Elemental microanalysis: VS% H% NOT% Cl% calculated 78.95 6.91 4.00 10.13 find 78,60 6.99 4.28 10.04

Stade L : 3- {2 - [(3aα, 11cα) -1,3,3a, 4,5,11c-Hexahydro-2H-naphtho [1,2-e] isoindol-2-yl] ethyl} -2-methyl- 4H-pyrido [1,2-a] pyrimidin-4-one, fumarate

The expected product is obtained according to the process described in Steps F and G of Example 1 from the compound obtained in the preceding stage. The product obtained is salified with fumaric acid. Elemental microanalysis: VS% H% NOT% calculated 70.49 5.88 7.85 find 70.84 5.94 7.99

EXAMPLE 7 : 3- [2 - ((3aα, 9bβ) -6,8-Dimethoxy-7-methyl-1,3a, 4,9b-tetrahydrochromo [3,4- vs ] Pyrrol-2 (3 H ) -Yl) -ethyl] -2-methyl-4 H pyrido [1,2- at ] pyrimidin-4-one, sesquifumarate Stage A : Methyl ester of trans- (3,5-dimethoxy-6-hydroxy-6-methyl) cinnamic acid

To 70 mmol of the compound obtained in Stage B of Example 2 in 100 ml of methanol are slowly added 205 mmol of a 30% solution of sodium methoxide in the methanol. The reaction medium is refluxed for 4 hours before being hydrolyzed with a 1N hydrochloric acid solution. The precipitate is filtered, washed with water and dried. to lead to the expected product.

Stage B (3aα, 9bβ) -2-Benzyl-6,8-dimethoxy-7-methyl-1,2,3,3a, 4,9b-hexahydrochromo [3,4-c] pyrrole, clilorhydrate

The expected product is obtained according to the process described in Steps C and D of Example 2 from the compound obtained in the preceding stage. Elemental microanalysis: VS% H% NOT% Cl% calculated 67.10 6.97 3.73 9.43 find 67,15 7.13 3.76 9.73

Stage C : 3- [2 - ((3aα, 9bβ) -6,8-Dimethoxy-7-methyl-1,3a, 4,9b-tetrahydrochromo [3,4-c] pyrrol-2 (3H) -yl) -ethyl ] -2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one, sesquifumarate

The expected product is obtained according to the process described in Steps F and G of Example 1 from the compound obtained in the previous stage. The product obtained is salified by the acid fumaric.

EXAMPLE 8 3- [2- (1,3a, 4,11c-Tetrahydrobenzo [5,6] chromeno [3,4- vs ] Pyrrol-2 (3 H ) -Yl) ethyl] -7-chloro-2-methyl-4 H pyrido [1,2- at ] Pyrimidin-4-one, fumarate Stage A 7-Chloro-3- (2-chloroethyl) -2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one

The product is prepared according to a protocol described in the literature (Liebigs Ann Chem. 1973, 103-110) using 2-amino-5-chloropyridine as starting reagent.

Stage B 3- [2- (1,3a, 4,11c-Tetrahydrobenzo [5,6] chromeno [3,4-c] pyrrol-2 (3H) -yl) ethyl] -7-chloro-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one, fumarate

The expected product is obtained according to the process described in Step G of Example 1 using the compound described in the preceding stage and the compound obtained in Step A of Example 3 (the product is salified with fumaric acid). Elemental microanalysis: VS% H% NOT% Cl% calculated 63.21 4.97 7.18 6.08 find 62.98 5.08 7.03 6.19

EXAMPLE 9 : 3- [2 - ((3aα, 9bα) -6,8-dimethoxy-7-methyl-1,3a, 4,9b-tetrahydrochromo [3,4-b] vs ] Pyrrol-2 (3 H ) -Yl) ethyl] -7-chloro-2-methyl-4 H pyrido [1,2- at ] Pyrimidin-4-one, fumarate

The expected product is obtained according to the process described in Example 2, using 7-chloro-3- (2-chloroethyl) -2-methyl- 4H- pyrido [1,2-α] pyrimidin as starting material. 4-one prepared in Step A of Example 8 instead of 3- (2-chloroethyl) -2-methyl- 4H- pyrido [1,2- a ] pyrimidin-4-one. The product obtained is salified with fumaric acid. Elemental microanalysis: VS% H% NOT% Cl% calculated 59.44 5.5 7.17 6.05 find 58.94 5.43 6.97 6.34

EXAMPLE 10 : 6- [2 - ((3aα, 9bα) -6-methoxy-1,3a, 4,9b-tetrahydrochromo [3,4-b] vs ] pyrrol-2 (3 H ) -Yl) ethyl] -7-methyl-5 H - [1,3] thiazolo [3,2 at ] Pyrimidin-5-one, fumarate Stage A : (3aα, 9bα) -6-Methoxy-1,2,3,3a, 4,9b-hexahydrochromeno [3,4-c] pyrrole

The product is prepared as in Steps A-F of Example 1 from cis- (2,3 dimethoxy) cinnamic.

Stage B : 6- [2 - ((3aα, 9bα) -6-Methoxy-1,3a, 4,9b-tetrahydrochromeno [3,4-c] pyrrol-2 (3H) -yl) ethyl] -7-methyl-5H - [1,3] thiazolo [3,2-a] pyrimidin-5-one, fumarate

The expected product is obtained from the compound prepared in the preceding stage according to the procedure used in Step G of Example 1, using 6- (2-chloroethyl) -7-methyl- 5H- [1,3] thiazolo [3,2- a ] pyrimidin-5-one. The product is salified with fumaric acid. Elemental microanalysis: VS% H% NOT% S% calculated 58.47 5.30 8.18 6.24 find 58.78 5.22 8.27 6.20

EXAMPLE 11 : 3- [2 - ((3aα, 9bα) -6-methoxy-1,3a, 4,9b-tetrahydrochromo [3,4-b] vs ] pyrrol-2 (3 H ) -Yl) ethyl] -2-methyl-4 H pyrido [1,2- at ] Pyrimidin-4-one, fumarate

The expected product is obtained according to the process described in Example 1, Stage G, using as starting materials the compound described in Step A of Example 10 and 3- (2-chloroethyl) -2-methyl- 4H - pyrido [1,2- a ] pyrimidin-4-one. The product obtained is salified with fumaric acid. Elemental microanalysis: VS% H% NOT% calculated 63.90 5.76 8.28 find 63.03 5.77 7.91

EXAMPLE 12 : 3- [2 - ((3aα, 9bα) -6-methoxy-1,3a, 4,9b-tetrahydrochromo [3,4-b] vs ] pyrrol-2 (3 H ) -Yl) ethyl] -7-bromo-2-methyl-4 H pyrido [1,2- at ] pyrimidin-4-one fumarate Stage A 3- (2-Chloroethyl) -7-bromo-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one

The product is prepared according to the process described in Step A of Example 8 using the 2-amino-5-bromopyridine as starting reagent.

Stage B : 3- [2 - ((3aα, 9bα) -6-methoxy-1,3a, 4,9b-tetrahydrochromeno [3,4-c] pyrrol-2 (3H) -yl) ethyl] -7-bromo-2 methyl-4H-pyrido [1,2-a] pyrimidin-4-one. fumarate

The expected product is obtained according to the process described in Example 11 from the compound of Example 10 and the pyrimidinone prepared in the preceding stage. The product is salified with fumaric acid. Elemental microanalysis: VS% H% NOT% Br% calculated 55,30 4.81 7.17 13.63 find 55.02 4.75 7.12 13.81

EXAMPLE 13 : 3- [2 - ((3aα, 11cα) -1,3a, 4,11c-tetrahydrobenzo [5,6] chromeno [3,4- vs ] pyrrol-2 (3 H ) -Yl) ethyl] -2,7-dimethyl-4 H pyrido [1,2- at ] Pyrimidin-4-one, fumarate Stage A 3- (2-Chloroethyl) -2,7-dimethyl-4H-pyrido [1,2-a] pyrimidin-4-one

The product is prepared according to the process described in Step A of Example 8 using the 2-amino-5-methylpyridine as starting reagent.

Stage B : 3- [2 - ((3aα, 11cα) -1,3a, 4,11c-Tetrahydrobenzo [5,6] chromeno [3,4-c] pyrrol-2 (3H) -yl) ethyl] -2,7 -dimethyl-4H-pyrido [1,2-a] pyrimidin-4-one, fumarate

The expected product is obtained according to the process described in Step G of Example 1 from the compound prepared in the preceding stage and the compound of Step A of Example 3. The product is salified with fumaric acid. Elemental microanalysis: VS% H% NOT% calculated 68.75 5.77 7.76 find 67.96 5.60 7.67

EXAMPLE 14 : 3- [2 - ((3aα, 9bα) -6,8-dimethoxy-7-methyl-1,3a, 4,9b-tetrahydrochromo [3,4-b] vs ] Pyrrol-2 (3 H ) -Yl) ethyl] -2,7-dimethyl-4 H pyrido [1,2 at ] pyrimidin-4-one, fumarate

The expected product is obtained according to the process described in Example 1, Stage G, using as starting materials the compound obtained in Step A of Example 13 and the product of Stage E of Example 2. The product is salified with fumaric acid. Elemental microanalysis VS% H% NOT% calculated 63.70 6, 24 7.43 find 63.57 6.09 7.36

EXAMPLE 15 : 3- [2 - ((3aα, 11cα) -1,3a, 4,11c-tetrahydrobenzo [5,6] chromeno [3,4- vs ] pyrrol-2 (3 H ) -Yl) ethyl] -7-bromo-2-methyl-4 H pyrido [1,2- at ] pyrimidin-4-one fumarate

The expected product is obtained according to the process described in Example 1, Stage G, using as starting materials the compound obtained Step A of Example 3 with the product obtained in Step A of Example 12. The product is salified with fumaric acid. Elemental microanalysis: VS% H% NOT% Br% calculated 59.41 4.65 6.93 13.18 find 59.04 4.69 6.81 12,93

EXAMPLE 16 : 3- [2 - ((3aα, 9bα) -6-Hydroxy-8-methoxy-7-methyl-1,3a, 4,9b-tetrahydrochromo [3,4- vs ] Pyrrol-2 (3 H ) -Yl) ethyl] -2-methyl-4 H pyrido [1,2- at ] Pyrimidin-4-one, fumarate Stage A : (3aα, 9bα) -2-Benzyl-8-methoxy-7-methyl-1,2,3,3a, 4,9b-hexahydrochromeno [3,4-c] pyrrol-6-ol

Add at 0 ° C, 64 ml of molar solution in dichloromethane of boron tribromide to a solution of 20 g of compound described in Step D of Example 2. After three hours stirring at 20 ° C., hydrolyze with 200 ml of saturated hydrogen carbonate solution sodium and decant the organic phase. The residue obtained is purified by chromatography on silica gel using as eluent a dichloromethane / methanol mixture: 98/2.

Stage B (3aα, 9bα) -8-Methoxy-7-methyl-1,2,3,3a, 4,9b-hexahydrochromeno [3,4-c] pyrrol-6-ol

The product prepared in the preceding stage is debenzylated by applying the operating mode described in Stage F of Example 1.

Stage C : 3- [2 - ((3a α, 9bα) -6-Hydroxy-8-methoxy-7-methyl-1,3a, 4,9b-tetrahydrochromo [3,4-c] pyrrol-2 (3H) -yl) ethyl] -2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one, fumarate

The expected product is obtained according to the process described in Step G of Example 1, using as starting reagent the compound described in the preceding stage and 3- (2-chloroethyl) -2-methyl- 4H- pyrido [1, 2- a ] pyrimidin-4-one. The product is salified with fumaric acid. Elemental microanalysis: VS% H% NOT% calculated 62.56 5.81 7.82 find 61.61 5.97 7.42

EXAMPLE 17 : 3- [4- (3aα, 11cα) -1,3a, 4,11c-tetrahydrobenzo [5,6] chromeno [3,4- vs ] pyrrol-2 (3 H ) -Yl) butyl] -2-methyl-4 H pyrido [1,2- at ] Pyrimidin-4-one, fumarate Stage A 3- (3-Butenyl) -2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one

For 2 hours at 160 ° C., a mixture of 5.7 g of methyl 2-acetyl-5-hexenoate, 3.15 g 2-aminopyridine and 0.65 g of polyphosphoric acid. Then add cold 30 ml water and extract with dichloromethane. The residue obtained after evaporation of the solvent is purified by chromatography on silica gel using eluting a dichloromethane / methanol mixture: 98/2.

Step B: 3-Butyl-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one

To a solution of 5.4 g of the product obtained in the previous step in 100 ml of tetrahydrofuran add 55.2 ml of a molar solution of borane in the tetrahydrofuran. After one hour cool to 0 ° C and add 10 ml of water then 25.4 g of sodium borate. Leave to agitate for one hour then concentrate everything, take up the residue in 100 ml of water and extract with dichloromethane. After evaporation of the solvent The residue obtained is purified by chromatography on silica gel using as eluent a dichloromethane / methanol mixture: 98/2.

Stage C 4- (2-Methyl-4-oxo-4H-pyrido [1,2-a] pyrimidin-3-yl) butanal

Reflux a mixture of 4.5 g of the product obtained in the previous step with 8.1 g of 1-hydroxy-1-oxo-benzo [ d ] [1,2] iodol-3-one in 200 ml. ml of tetrahydrofuran. Filter cold and concentrate the filtrate.

Stage D : 3- [4- (3aα, 11α) -1,3a, 4,11c-Tetrahydrobenzo [5,6] chromeno [3,4-c] pyrrol-2 (3H) -yl) butyl] -2-methyl- 4H-pyrido [1,2-a] pyrimidin-4-one

The rest of the synthesis is carried out by applying the procedure described in Step B of Example 5 from the aldehyde obtained in the preceding stage.
The product is salified by fumaric acid Elemental microanalysis: VS% H% NOT% calculated 68.06 5.89 7.26 find 67.25 5.85 6.82

EXAMPLE 18 : 3- [2 - ((3aα, 11cα) -1,3a, 4,11c-tetrahydrobenzo [5,6] chromeno [3,4- vs ] pyrrol-2 (3 H ) -Yl) ethyl] -2-methyl-4 H pyrido [1,2- at ] Pyrimidin-4-one, fumarate Stage A : (3aα, 11cα) -1,2,3,3a, 4,11c-Hexahydrobenzo [5,6] chromeno [3,4-c] pyrrole

Duplication of racemate 1,2,3,3a, 4,11c-hexahydrobenzo [5,6] chromeno [3,4- c ] pyrrole: Dissolve 53.6 g of the product obtained in Step A of Example 3 in 450 ml ethanol and bring everything to reflux. Add a solution of 85.2 g of (+) 2,3-dibenzoyl-D-tartaric acid in 450 ml of ethanol. Filter the precipitate 12 hours later. Recrystallize this precipitate three times in an ethanol / water mixture: 85/15. The compound is obtained in base form after treatment with aqueous sodium hydroxide.

Stage B : 3- [2 - ((3aα, 11cα) -1,3a, 4,11c-Tetrahydrobenzo [5,6] chromeno [3,4-c] pyrrol-2 (3H) -yl) ethyl] -2-methyl -4H-pyrido [1,2-a] pyrimidin-4-one, fumarate

The expected product is obtained according to the process described in Step G of Example 1, using as starting materials the enantiomer prepared in the preceding stage and 3- (2-chloroethyl) -2-methyl- 4H- pyrido [1 2- [ a ] pyrimidin-4-one.
The product is salified by fumaric acid Elemental microanalysis: VS% H% NOT% calculated 68.30 5.54 7.96 find 68.24 5.41 8.12

EXAMPLE 19 : 3- [2 - ((3aβ, 11cβ) -1,3a, 4,11c-tetrahydrobenzo [5,6] chromeno [3,4- vs ] pyrrol-2 (3 H ) -Yl) ethyl] -2-methyl-4 H pyrido [1,2- at ] Pyrimidin-4-one, fumarate Stage A (3aβ, 11cβ) -1,2,3,3a, 4,11c-Hexahydrobenzo [5,6] chromeno [3,4-c] pyrrole

Duplication of the racemate: 1,2,3,3a, 4,11c-hexahydrobenzo [5,6] chromeno [3,4- c ] pyrrole Dissolve 10.3 g of the product obtained in Step A of Example 3 in 200 ml ethanol and bring everything to reflux. Add a solution of 16.4 g of (-) 2,3-dibenzoyl-L-tartaric acid in 200 ml of ethanol. Filter the precipitate 12 hours later. Recrystallize this precipitate three times in an ethanol / water mixture: 85/15. The compound is obtained in base form after treatment with aqueous sodium hydroxide.

Stage B : 3- [2 - ((3aβ, 11cβ) -1,3a, 4,11c-Tetrahydrobenzo [5,6] chromeno [3,4-c] pyrrol-2 (3H) -yl) ethyl] -2-methyl -4H-pyrido [1,2-a] pyrimidin-4-one, fumarate

The expected product is obtained according to the process described in Step G of Example 1, using as starting materials the enantiomer prepared in the preceding stage and 3- (2-chloroethyl) -2-methyl- 4H- pyrido [1 2- [ a ] pyrimidin-4-one.
The product is salified by fumaric acid Elemental microanalysis: VS% H% NOT% calculated 68.30 5.54 7.96 find 68.85 5.45 7.81

EXAMPLE 20 : 3- [2 - ((3aα, 9bα) -6,8-Dimethoxy-7-propyl-1,3a, 4,9b-tetrahydrochromo [3,4-b] vs ] Pyrrol-2 (3 H ) -Yl) ethyl] -2-methyl-4 H pyrido [1,2- at ] pyrimidin-4-one fumarate Stage A : 2-Allyloxy-4-methoxybenzaldehyde

To a solution of 100 g of 2-hydroxy-4-methoxy benzaldehyde in 2 liters of acetone add 79.5 ml of allyl bromide and then gradually 272 g of potassium carbonate. Carry 4 hours at reflux and then filter, concentrate under vacuum the filtrate, take up the residue with 1 1 of dichloromethane and wash this solution with a solution of sodium hydroxide normal and then with a solution of saturated sodium chloride. Dry on sulphate magnesium and concentrate under vacuum.

Stage B : 3-Allyl-2-hydroxy-4-methoxybenzaldehyde

Heat at 200 ° C. for 15 hours a solution of 125 g of the product obtained in Stage A in 300 ml of N, N- dimethylaniline. Evaporate the solvent in vacuo, take up the residue in 1 l of isopropyl ether, extract this solution 10 times with 100 ml of normal sodium hydroxide solution, then acidify all of these extracts with the aid of 3N hydrochloric acid. Then extract the acidic aqueous solution with dichloromethane, dry and concentrate the organic phase.

Stage C : 3-Allyl-2,4-dimethoxybenzaldehyde

Bring to reflux for 5 hours a mixture of 108 g of the product obtained in the previous stage, 74.4 g. of dimethyl sulfate, 233 g of potassium carbonate in 2 l of acetone. Filter cold and concentrate the resulting solution. The residue is taken up in isopropyl ether, washed with a saturated solution of sodium hydrogencarbonate and then with water. Dry on sulphate magnesium and evaporate the solvent in vacuo. The residue is purified by chromatography on silica gel using cyclohexane / ethyl acetate: 96/4 as eluent.

Stage D 2,4-Dimethoxy-3-propylbenzaldehyde

64 g of the product obtained in Stage C are hydrogenated at ambient temperature and at atmospheric pressure using 35 g of Wilkinson catalyst ( tris- triphenylphosphine rhodium chloride) in 500 ml of benzene. The product is purified by chromatography on silica gel using as eluent a cyclohexane / ethyl acetate mixture: 92/8.

Stadium E : 3- [2 - ((3aα, 9bα) -6,8-Dimethoxy-7-propyl-1,3a, 4,9b-tetrahydro chromeno [3,4-c] pyrrol-2 (3H) -yl) ethyl] -2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one fumarate

The rest of the synthesis is carried out by applying the procedures described in Example 2 (stages A to F) using the aldehyde obtained in the previous stage as starting reagent.
The product is salified with fumaric acid. Elemental microanalysis VS% H% NOT% calculated 64.24 6.43 7.25 find 63.33 6.30 7.05

EXAMPLE 21 : 3- [2 - ((3aα, 11cα) -1,3a, 4,11c-tetrahydrobenzo [5,6] chromeno [3,4- vs ] pyrrol-2 (3 H ) -Yl) ethyl] -7-chloro-2-methyl-4 H pyrido [1,2- at ] Pyrimidin-4-one, fumarate Stage A (7-Chloro-2-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidin-3-yl) acetaldehyde

The product is prepared following the procedure described in Step C of Example 18 using 7-chloro-3- (2-hydroxyethyl) -2-methyl- 4H- pyrido [1,2- a ] pyrimidine. 4-one as starting substrate obtained according to a method described in the literature (Liebigs Ann Chem 1973, 103-110).

Stage B : 3- [2 - ((3aα, 11cα) -1,3a, 4,11c-Tetrahydrobenzo [5,6] chromeno] 3,4-c] pyrrol-2 (3H) -yl) ethyl] -7-chloro -2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one, fumarate

The expected product is obtained according to the process described in Stage B of Example 5, using the compound prepared in Stage A of Example 19 and the aldehyde prepared in the preceding stage. The product is salified with fumaric acid. Elemental microanalysis: VS% H% NOT% Cl% calculated 64.11 5.02 7.48 6.31 find 63.82 5.02 7.35 6.63

EXAMPLE 22 : 3- [2 - ((3aβ, 11cβ) -1,3a, 4,11c-tetrahydrobenzo [5,6] chromeno [3,4- vs ] pyrrol-2 (3 H ) -Yl) ethyl] -7-chloro-2-methyl-4 H pyrido [1,2- at ] Pyrimidin-4-one, fumarate

The expected product is obtained according to the process described in Step B of Example 5, using the compound prepared in Step A of Example 20 and the aldehyde prepared in Step A of Example 22. The product is salified with the product. fumaric acid. Elemental microanalysis VS% H% NOT% Cl% calculated 64.11 5.02 7.48 6.31 find 64.30 4.92 7.53 6.56

EXAMPLE 23 : 3- [2 - ((3aα, 11cα) -1,3a, 4,11c-tetrahydrobenzo [5,6] chromeno [3,4- vs ] pyrrol-2 (3 H ) -Yl) ethyl] -2-methyl-4-oxo-4 H pyrido [1,2- at ] Pyrimidine-7-carbonitrile, fumarate

To a solution of 1.83 mmol of the compound obtained in Example 15 in 12 ml of dimethylformamide is added, under an inert atmosphere, 1.1 mmol of zinc cyanide and 0.073 mmol of palladium tetrakis triphenylphospine. Heat the reaction medium for 12 hours at 90 ° C. Evaporate the reaction medium, take up with methylene chloride, filter through celite and evaporate. The residue obtained is purified by chromatography on silica (eluent: dichloromethane / methanol 95/5). The product is salified with fumaric acid. Elemental microanalysis: VS% H% NOT% calculated 68.52 5.18 10.58 find 68.63 5.05 10.58

EXAMPLE 24 : 3- [2 - ((3aα, 11cα) -1,3a, 4,11c-tetrahydrobenzo [5,6] chromeno [3,4- vs ] pyrrol-2 (3 H ) -Yl) ethyl] -2-methyl-7- (2-thienyl) -4 H pyrido [1,2- at ] pyrimidin-4-one fumarate Stage A 3- (2-Hydroxyethyl) -2-methyl-7- (2-thienyl) -4H-pyrido [1,2-a] pyrimidin-4-one

Mix in a flask under a stream of argon 5 g of 7-bromo-3- (2-hydroxyethyl) -2-methyl-4 H -pyrido [1,2- a ] pyrimidin-4-one, 6.2 ml of tributylthiophen-2-yl-stannane, 1 g of palladium tetrakis triphenylphosphine and 250 ml of N- methylpyrrolidone. Bring this solution to 130 ° C. for 2 hours, then evaporate the solvent in vacuo, take up the residue in 200 ml of dichloromethane, wash the solution with 10% potassium fluoride solution, filter, decant the organic phase and wash it with water. the water. After drying over magnesium sulphate and evaporation, the residue obtained is purified by chromatography on silica gel, using a 95/5 dichloromethane / methanol mixture as eluent.

Stage B 3- (2-Chloroethyl) -2-methyl-7- (2-thienyl) -4H-pyrido [1,2-a] pyrimidin-4-one

The product of the previous stage is transformed into a chlorinated derivative by applying a mode described in the literature (Liebigs Ann.Chem 1973, 103-110).

Stage C : 3- [2 - ((3aα, 11cα) -1,3a, 4,11c-Tetrahydrobenzo [5,6] chromeno [3,4-c] pyrrol-2 (3H) -yl) ethyl] -2-methyl -7- (2-thienyl) -4H-pyrido [1,2-a] pyrimidin-4-one, fumarate

The rest of the synthesis is carried out by applying the procedure described in Example 1 (Stage G) using the product obtained in the preceding stage in place of 3- (2-chloroethyl) -2-methylpyrido [1,2- a ] pyrimidin-4-one. The product is salified with fumaric acid. Elemental microanalysis: VS% H% NOT% S% calculated 66.98 5.12 6.89 5.26 find 66,02 5.07 6.85 4.94

EXAMPLE 25 : 3- [2 - ((3aβ, 11cα) -1,3a, 4,11c-tetrahydrobenzo [5,6] chromeno [3,4- vs ] pyrrol-2 (3 H ) -Yl) ethyl] -7-chloro-2-methyl-4 H pyrido [1,2- at ] Pyrimidin-4-one, hemifumarate Stage A (3aβ, 11cα) -1,2,3,3a, 4,11c-Hexahydrobenzo [5,6] chromeno [3,4-c] pyrrole

This compound is obtained according to the same experimental protocol as that described in patent application EP 691 342 (example 33).

Stage B : 3- [2 - ((3aβ, 11cα) -1,3a, 4,11c-Tetrahydrobenzo [5,6] chromeno [3,4-c] pyrrol-2 (3H) -yl) ethyl] -7-chloro -2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one, hemifumarate

The expected product is obtained according to the process described in Step G of Example 1, using the compound described in the preceding stage and the compound obtained in Step A of Example 8 (the product is salified with fumaric acid). Elemental microanalysis: VS% H% NOT% Cl% calculated 66.16 5.16 8.15 6.88 find 66,33 5.10 8.31 7.40

EXAMPLE 26 : 6- [2 - ((3aβ, 11cα) -1,3a, 4,11c-tetrahydrobenzo [5,6] chromeno [3,4- vs ] pyrrol-2 (3 H ) -Yl) ethyl] -7-methyl-5 H - [1,3] thiazolo [3,2 at ] Pyrimidin-5-one, hemifumarate

The expected product is obtained according to the process described in Step G of Example 1, using the compound obtained in Step A of Example 26 with 6- (2-chloroethyl) -7-methyl-5 H - [1, 3] thiazolo [3,2- a ] pyrimidin-5-one (the product is salified with fumaric acid). Elemental microanalysis: VS% H% NOT% Cl% calculated 65.09 5.26 8.63 6.58 find 64.98 5.28 8.61 6.67

EXAMPLE 27 : 3- [2 - ((3aβ, 11cα) -1,3a, 4,11c-tetrahydrobenzo [5,6] chromeno [3,4- vs ] pyrrol-2 (3 H ) -Yl) ethyl] -2-methyl-4 H pyrido [1,2- at ] Pyrimidin-4-one, hemifumarate

The expected product is obtained according to the process described in Step G of Example 1, using the compound described in Step A of Example 26 with 3- (2-chloroethyl) -2-methylpyrido [1,2- a]. ] pyrimidin-4-one (the product is salified with fumaric acid). Elemental microanalysis: VS% H% NOT% calculated 70.90 5.74 8.73 find 70.99 5.70 8.77

PHARMACOLOGICAL STUDY EXAMPLE A : Test of penile erections in rats

The test evaluates the ability of pharmacological agents to inhibit penile erection caused by administration of a selective 5-HT _2c agonist, RO 60-0175.

Male Wistar strain rats weighing 120-140 g on the day of the experiment, are placed individually in plexiglass observation boxes, just after receiving the compound to be tested or the vehicle. Thirty minutes later, the animals receive the RO 60-0175 (1.25 mg / kg, subcutaneous) and the number of erections performed during Next 30 minutes is counted.

Results : It appears that the compounds of the invention are capable of inhibiting penile erections caused by administration of the selective 5-HT _2c agonist. They therefore have an antagonistic character at the 5-HT _2c receptors. By way of example, the compound of Example 3 has an inhibitory dose of 50 (ID ₅₀ ) of 2.6 mg / kg, sc

EXAMPLE B : Isolation-induced aggressiveness test in mice

The animals used are male CD-1 mice. Upon arrival, the mice are isolated in individual cages with food and drink at will. After a period of one month isolated, aggressively stable pairs of mice are selected by observing, when confronted, latency, number and duration of attacks.

The test takes place once a week. On the day of the test, each mouse of the pair (resident and intruder) receives an intraperitoneal injection of the vehicle (control animals) or test product (treated animals) at a volume of 10 ml / kg. After 30 minutes, the intruder mouse is introduced into the cage of the resident mouse. The latency of the first attack, the number and duration of attacks are then measured for a period of three minutes.
A product is considered specifically antiaggressive when it decreases the number and duration of attacks at non-sedating doses.

Results : It appears that the compounds of the invention significantly reduce the number and duration of attacks. By way of example, the compound of Example 3 has a 50 (ID ₅₀ ) inhibitory dose of 7 mg / kg, ip.

EXAMPLE C : Mouse burrow test in mice

The test evaluates the ability of pharmacological agents to inhibit behavior spontaneous burial of bots in the mouse, this inhibition being predictive of actions antidepressant and / or anti-impulsive.

Male NMRI strain mice weighing 20 to 25 g on the day of the experiment are placed individually in macrolon boxes containing 5 cm of sawdust and covered with perforated plexiglass plate. Twenty-four glass balls "cat's eye" are distributed regularly on the sawdust on the periphery of the box. After 30 minutes of exploration free, the animals are removed from the box and the number of buried logs is counted.

Results : It appears that the compounds of the invention inhibit the spontaneous behavior of burial of beads in mice. By way of example, the compound of Example 3 has an inhibitory dose of 50 (ID ₅₀ ) of 4.1 mg / kg, sc

EXAMPLE D : Determination of affinity for α receptors ₂ adrenergic in the rat

The affinity was determined by competition experiments with ^[3 H]-RX 821.002. The membranes are prepared from rat cerebral cortex and incubated in triplicate with 0.4 nM [ ³ H] -RX 821.002 and the test compound in a final volume of 1.0 mL, for 60 minutes at 22 ° C. The incubation buffer contains 50 nM TRIS-HCl (pH 7.5), 1 mM EDTA and 100 μM GppNHp. Nonspecific binding is determined with 10 μM phentolamine.

Data Analysis: At the end of the incubation, the incubation medium is filtered through WHATMAN GF / B filters impregnated with 0.1% polyethylenimine and washed three times with 5 ml of cooled buffer. The radioactivity retained on the filters is determined by counting the scintillation liquid. The binding isotherms are analyzed by nonlinear regression.

Results : The compounds of the invention interact specifically with α ₂ -adrenergic receptors with, for example for the compound of Example 3, a pK _i of 7.5.

EXAMPLE E : Pharmaceutical Composition Preparation formula for 1000 tablets dosed at 10 mg

Composed of example 3 10 g hydroxypropyl 2 g Wheat starch 10 g Lactose 10 g Magnesium stearate 3 g Talc 3 g

Claims (13)

1. Compounds of formula (I) :

   

   wherein :

   

   R₁, R₂, R₃ and R₄, which may be the same or different, each represent a hydrogen atom, a halogen atom or a group selected from linear or branched (C₁-C₆)alkyl, linear or branched (C₁-C₆)alkoxy, linear or branched (C₁-C₆)polyhaloalkyl, hydroxy, cyano, nitro and amino,
   or R₁ with R₂, R₂ with R₃, or R₃ with R₄, together with the carbon atoms carrying them, form an optionally substituted benzene ring or an optionally substituted heteroaromatic ring,

   X represents an oxygen atom or a methylene group,

   A represents a linear or branched (C₁-C₆)alkylene chain,

   

   represents an unsaturated nitrogen-containing heterocycle optionally substituted by one or two identical or different substituents selected from halogen atoms and linear or branched (C₁-C₆)alkyl, hydroxy, linear or branched (C₁-C₆)alkoxy, linear or branched (C₁-C₆)polyhaloalkyl, cyano, nitro, amino, optionally substituted phenyl, optionally substituted thienyl, optionally substituted furyl and optionally substituted pyrrolyl groups,

   and R₅ represents a linear or branched (C₁-C₆)alkyl group,
   their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base,

   it being understood that :

   the term "(C₁-C₆)alkyl" denotes a hydrocarbon chain containing from one to six carbon atoms,

   the term "(C₁-C₆)alkoxy" denotes a (C₁-C₆)alkyl-oxy group containing from one to six carbon atoms,

   the term "(C₁-C₆)alkylene" denotes a bivalent hydrocarbon chain containing from one to six carbon atoms,

   the term (C₁-C₆)polyhaloalkyl denotes a carbon chain containing from one to six carbon atoms and from 1 to 9 halogen atoms,

   the term "heteroaromatic ring" denotes a 5- or 6-membered aromatic ring containing one, two or three hetero atoms selected from oxygen, nitrogen and sulphur,

   the term "unsaturated nitrogen-containing heterocycle" denotes a 5- to 7-membered unsaturated ring having one, two or three unsaturated bonds and containing one, two or three hetero atoms, one of those hetero atoms being the nitrogen atom and the additional hetero atom(s) optionally present being selected from oxygen, nitrogen and sulphur atoms,

   the term "optionally substituted" applied to the expressions "benzene ring", "heteroaromatic ring", "phenyl", "thienyl", "furyl" or pyrrolyl" indicates that those groups are optionally substituted by one or two identical or different substituents selected from halogen atoms and linear or branched (C₁-C₆)alkyl, hydroxy, linear or branched (C₁-C₆)alkoxy, linear or branched (C₁-C₆)polyhaloalkyl, cyano, nitro and amino groups.
2. Compounds of formula (I) according to claim 1, wherein R₁, R₂, R₃ and R₄, which may be the same or different, each represent a hydrogen atom or a linear or branched (C₁-C₆)alkyl, linear or branched (C₁-C₆)alkoxy or hydroxy group, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
3. Compounds of formula (I) according to claim 1, wherein R₁ and R₂, together with the carbon atoms carrying them, form a benzene ring and R₃ and R₄ each represent a hydrogen atom, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
4. Compounds of formula (I) according to any one of claims 1 to 3, wherein X represents an oxygen atom, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
5. Compounds of formula (I) according to any one of claims 1 to 4, wherein A represents an ethylene, propylene or butylene chain, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
6. Compounds of formula (I) according to any one of claims 1 to 5, wherein

   

   represents the following group

   

   optionally substituted by one or two identical or different substituents selected from halogen atoms and linear or branched (C₁-C₆)alkyl, hydroxy, linear or branched (C₁-C₆)alkoxy, linear or branched (C₁-C₆)polyhaloalkyl, cyano, nitro, amino and thienyl groups, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
7. Compounds of formula (I) according to any one of claims 1 to 5, wherein

   

   represents the following group

   

   optionally substituted by one or two identical or different substituents selected from halogen atoms and linear or branched (C₁-C₆)alkyl, hydroxy, linear or branched (C₁-C₆)alkoxy, linear or branched (C₁-C₆)polyhaloalkyl, cyano, nitro and amino groups, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
8. Compounds of formula (I) according to any one of claims 1 to 6, wherein A represents an ethylene chain, X represents an oxygen atom, R₅ represents a methyl group and

   

   represents the following group

   

   optionally substituted in the 2'-position by a halogen atom or a group selected from linear or branched (C₁-C₆)alkyl, cyano and thienyl, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
9. Compound of formula (I) according to any one of claims 1 to 2, 4 to 6 and 8, which is 3-[2-((3aα,9bα)-9-methoxy-1,3a,4,9b-tetrahydrochromeno[3,4-c]pyrrol-2(3H-yl)-ethyl]-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, its enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid.
10. Compounds of formula (I) according to any one of claims 1, 3 to 6 and 8, which are 3-[2-((3aα,11cα)-1,3a,4,11c-tetrahydrobenzo[5,6]chromeno[3,4-c]pyrrol-2(3H)-yl)-ethyl]-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one and 3-[2-((3aβ,11cα)-1,3a,4,11c-tetrahydrobenzo[5,6]chromeno[3,4-c]pyrrol-2(3H)-yl)ethyl]-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, their enantiomers, and addition salts thereof with a pharmaceutically acceptable acid.
11. Process for the preparation of compounds of formula (I) according to claim 1,
    characterised in that a compound of formula (II) :

    

       wherein R₁, R₂, R₃, R₄ and X are as defined for formula (I),
    is subjected to catalytic hydrogenation to yield the compound of formula (III) :

    

       wherein R₁, R₂, R₃, R₄ and X are as defined hereinbefore,
    which is reacted either with a compound of formula (IV) :

    

       wherein A, B and R₅ are as defined for formula (I) and Y₁ represents a leaving group such as, for example, a halogen atom or a tosylate, triflate or mesylate group,
    or, under conditions of reductive amination, with a compound of formula (V) :

    

       wherein B and R₅ are as defined for formula (I) and A' represents a bond or a linear or branched (C₁-C₅)alkylene chain,
    to yield the compound of formula (I), which is purified, if necessary, according to a conventional purification technique, which is separated, if desired, into its stereoisomers according to a conventional separation technique, and which is converted, if desired, into addition salts thereof with a pharmaceutically acceptable acid or base.
12. Pharmaceutical composition comprising as active ingredient a compound according to any one of claims 1 to 10, in combination with one or more inert, non-toxic, pharmaceutically acceptable excipients or carriers.
13. Pharmaceutical composition according to claim 12 for use as a double α₂/5-HT_2c antagonist medicament in the treatment of depression, impulsive behaviour disorders, anxiety, schizophrenia, Parkinson's disease, cognitive disorders, disturbances of libido, sexual dysfunctions, appetite disorders and sleep disorders.